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United States Patent |
5,266,583
|
Ohtawa
|
November 30, 1993
|
Angitotensin II antagonist
Abstract
A human urinary metabolite of Losartan has been isolated and identified as
structure I.
##STR1##
This compound is an active angiotensin II receptor antagonist useful in
the treatment of hypertension and congestive heart failure.
Inventors:
|
Ohtawa; Masakatsu (Tokyo, JP)
|
Assignee:
|
Merck & Co., Inc. (Rahway, NJ)
|
Appl. No.:
|
940253 |
Filed:
|
September 1, 1992 |
Current U.S. Class: |
514/381; 548/253 |
Intern'l Class: |
C07D 403/10; A61K 031/41 |
Field of Search: |
514/381
548/253
|
References Cited
Foreign Patent Documents |
0459136 | Dec., 1991 | EP | 548/253.
|
Primary Examiner: Springer; David B.
Attorney, Agent or Firm: North; Robert J., Nicholson; William H., DiPrima; Joseph F.
Claims
What is claimed is:
1. A compound of structural formula:
##STR4##
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical formulation for the treatment of hypertension
comprising a pharmaceutically acceptable carrier and an effective amount
of the compound of claim 1.
3. A method of treating hypertension and congestive heart failure which
comprises the administration of an effective amount of the compound of
claim 1 to a patient in need of such treatment.
Description
BACKGROUND OF THE INVENTION
Losartan is a well known angiotensin-II receptor antagonist of structural
formula II. It is also known to be metabolized to the compound of
Structure III.
##STR2##
Now with the present invention there is provided another metabolite of
Losartan of Structure I which is an active angiotensin II receptor
antagonist.
DETAILED DESCRIPTION OF THE INVENTION
The novel compound of this invention has Structural formula I:
##STR3##
or a pharmaceutically acceptable salt thereof.
The novel compound of this invention was first isolated from 500 ml urine
sample collected after single oral administration of 200 mg/man of
Losartan (II) to humans. The methods for the separation of the compound
comprised three steps.
The first step was rough separation of the compound by extracting with two
sample-volume of t-butyl methyl ether (TBME) twice under acidic conditions
and subjecting the extract to preparative HPLC. The chromatographic
conditions were as follows:
Guard Column: Senshu Pak ODS-1031-N 4.6 mm.times.30 mm
Separation Column: Senshu Pak ODS-4251-N 10 mm.times.250 mm
Column Temp.: 40.degree. C.
Mobile Phase:
A; CH.sub.3 CN, B: 25 mM phosphate buffer (pH 2.8)
A:B=51:49.fwdarw.72:28 gradient for 40 min.
Flow Rate: 2.0 ml/min.
Detector: 310 nm
Retention Time: 9-11 min.
The fraction corresponding to the peaks (retention time 9-11 min) on HPLC
were collected.
The second step was further separation of the compound obtained from the
rough fraction by extraction with TBME and reseparation by the preparative
HPLC with the following conditions:
Guard Column: Senshu Pak ODS-1031-N 4.6 mm.times.30 mm
Separation Column: Senshu Pak ODS-4251-N 10 mm.times.250 mm
Column Temp.: 40.degree. C.
Mobile Phase:
A; CH.sub.3 CN, B: 25 mM phosphate buffer (ph 2.8)
A:B=30:70 for 7.5 min.; 30:70.fwdarw.40:60 gradient for 7.5 min.; 40:60 for
20 min.
Flow Rate:
1.8 ml/min for 7.5 min.
2.0 ml/min to finish
Detector: 230 nm
Retention Time: about 29 min.
The last step was the purification by TLC. The peak fraction having
retention time at 29 min. on the HPLC was collected ans applied to TLC
plate. TLC was carried out on precoated silica-gel glass plate, 0.25 mm
thickness. The developing solvent was as follows: CHCl.sub.3 /MeOH/AcOH
(30/3/1,v/v/v). After development, the compound was visualized under UV
light. The appropriate area (Rf value 0.2) on the silica-gel plate was
removed and eluted with methanol. The purified metabolite was analyzed by
HPLC. The chromatographic conditions were as follows:
Column:
Pre; MPLC NewGuard RP-18, 15 mm.times.3.2 mm I.D.
Sep: CAPCELL PAK C18, 250 mm.times.4.6 mm I.D.
Column Temp.: 40.degree. C.
Mobile Phase:
A; CH.sub.3 CN, B: 25 mM phosphate buffer (pH 2.8)
A:B=20:80.fwdarw.30:70 gradient for 15 min.; 30:70.fwdarw.45:55 gradient
for 15 min.
Flow Rate: 1.0 ml/min.
Detector: 230 nm
Retention Time: about 25.8 min.
The structure of the metabolite was assigned based upon mass and
spectroscopic analysis.
In the FAB mass spectrum of I, there is a protonated molecular ion at m/z
453 and a benzylic methylene proton signal at 5.65 ppm in the nmr
spectrum. However, the signals corresponding to the 2-butyl sidechain
protons of II were present and the aromatic ring protons which appeared at
7.42-7.55 ppm in II were shifted upfield to 6.88-7.21 ppm. The proton
decoupling indicated that this metabolite is substituted at the position
corresponding to either biphenyl-C4' or -C5' of II. Further the NOESY
experiment showed that this metabolite is substituted at the biphenyl
-C4'. From these results, the metabolite was assigned the Structure I.
The compound of this invention forms salts with various inorganic and
organic acids and bases which are also within the scope of the invention.
Such salts include ammonium salts, alkali metal salts such as sodium and
potassium salts, alkaline earth metal salts like the calcium and magnesium
salts, salts with organic bases; e.g., dicyclohexylamine salts,
N-methyl-D-glucamine salts, salts with amino acids like arginine, lysine,
and the like. Also, salts with organic and inorganic acids may be
prepared; e.g., HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4,
methanesulfonic, toluensulfonic, maleic, fumaric, camphorsulfonic. The
non-toxic, physiologically, acceptable salts are preferred, although other
salts are also useful; e.g., in isolating or purifying the product.
The salts can be formed by conventional means such as by reacting the free
acid or free base forms of the product with one or more equivalents of the
appropriate base or acid in a solvent or medium in which the salt is
insoluble, or in a solvent such as water which is then removed in vacuo or
by freeze-drying or by exchanging the cations of an existing salt for
another cation on a suitable ion exchange resin.
The compound of this invention is useful in treating hypertension. It is
also of value in the management of acute and chronic congestive heart
failure and angina. It is also expected to be useful in primary and
secondary hyperaldosteronism, renal diseases such as diabetic nephropathy,
glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive
nephrosclerosis, end stage renal disease, renal transplant therapy,
renovascular hypertension, scleroderma, left ventricular dysfunction,
systolic and diastolic dysfunction diabetic retinopathy, in the management
of vascular disorders such as migraine or Raynaud's disease, as
prophylaxis to minimize the atherosclerotic process, in neointimal
hyperplasia following angioplasty or vascular injury and to retard the
onset of type II diabetes. The application of the compound of this
invention for these and similar disorders will be apparent to those
skilled in the art.
The compound of this invention is also useful to treat elevated intraocular
pressure and to enhance retinal blood flow and can be administered to
patients in need of such treatment with typical pharmaceutical
formulations such as tablets, capsules, injectables and the like as well
as topical ocular formulations in the form of solutions, ointments,
inserts, gels, and the like. Pharmaceutical formulations prepared to treat
intraocular pressure would typically contain about 0.1% to 15% by weight,
preferably 0.5% to 2% by weight, of the compound of this invention. For
this use, the compound of this invention may also be used in combination
with other medications for the treatment of glaucoma including choline
esterase inhibitors such as physostigmine salicylate or demecarium
bromide, parasympathomimetic agents such as pilocarpine nitrate,
.beta.-adrenergic antagonists such as timolol maleate, adrenergic agonists
such as epinephrine and carbonic anhydrase inhibitors such as TRUSOPT.TM..
In the management of hypertension and the clinical conditions noted above,
the compound of this invention may be utilized in compositions such as
tablets, capsules or elixirs for oral administration, suppositories for
rectal administration, sterile solutions or suspensions for parenteral or
intramuscular administration, and the like. The compound of this invention
can be administered to patients (animals and human) in need of such
treatment in dosages that will provide optimal pharmaceutical efficacy.
Although the dose will vary from patient to patient depending upon the
nature and severity of disease, the patient's weight, special diets then
being followed by a patient, concurrent medication, and other factors
which those skilled in the art will recognize, the dosage range will
generally be about 1 to 1000 mg. per patient per day which can be
administered in single or multiple doses. Preferably, the dosage range
will be about 5.0 to 500 mg. per patient per day; more preferably about 5
to 300 mg. per patient per day.
The compound of this invention can also be administered in combination with
other antihypertensives and/or diuretics. For example, the compound of
this invention can be given in combination with diuretics such as
hydrochlorothiazide, chlorothiazide, chlorthalidone, methyclothiazide,
furosemide, ethacrynic acid, triamterene, amiloride, atriopeptin and
spironolactone; calcium channel blockers, such as diltiazem, felodipine,
nifedipine, amlodipine, nimodipine, isradipine, nitrendipine and
verapamil; .beta.-adrenergic antagonists such as timolol, atenolol,
metoprolol, propanolol, nadolol and pindolol; angiotensin converting
enzyme inhibitors such as enalapril, lisinopril, captopril, ramipril,
quinapril and zofenopril; renin inhibitors such as A-69729 and FK 906 and
FK 744; .alpha.-adrenergic antagonists such as prazosin, doxazosin, and
terazosin; sympatholytic agents such as methyldopa, clonidine and
guanabenz, atriopeptidase inhibitors (alone or with ANP) such as UK-79300;
serotonin antagonists such as ketanserin; A.sub.2 -adenosine receptor
agonists such as CGS 22492C; potassium channel agonists such as pinacidil
and cromakalim; and various other antihypertensive drugs including
reserpine, minoxidil, guanethidine, hydralazine hydrochloride and sodium
nitroprusside as well as combinations of the above-named drugs.
Combinations useful in the management of congestive heart failure include,
in addition, the compound of this invention with cardiac stimulants such
as dobutamine and xamoterol and phosphodiesterase inhibitors including
amrinone and milrinone.
Typically, the individual daily dosages for these combinations can range
from about one-fifth of the minimally recommended clinical dosages to the
maximum recommended levels for the entities when they are given singly.
To illustrate these combinations, the angiotensin II antagonist of this
invention can be effectively combined at levels of the 1.0-500 milligrams
per day range with the following compounds at the indicated per day dose
range: hydrochlorothiazide (6-100 mg), chlorothiazide (125-500 mg),
ethacrynic acid (5-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),
propanolol (10-480 mg), timolol maleate (1-20 mg), methyldopa (125-2000
mg), felodipine (1-20 mg), nifedipine (5-120 mg), nitrendipine (5-60 mg)
and diltiazem (30-540 mg). In addition, triple drug combinations of
hydrochlorothiazide (5-100 mg) plus amiloride (5-20 mg) plus the compound
of this invention (1-500 mg) or hydrochlorothiazide (5-100 mg) plus
timolol maleate (5-60) plus the compound of this invention (1-500 mg) or
hydrochlorothiazide (5-200 mg) and nifedipine (5-60 mg) plus the compound
of this invention (1-500 mg) are effective combinations to control blood
pressure in hypertensive patients. Naturally, these dose ranges can be
adjusted on a unit basis as necessary to permit divided daily dosage and,
as noted above, the dose will vary depending on the nature and severity of
the disease, weight of patient, special diets and other factors.
Typically, these combinations can be formulated into pharmaceutical
compositions as discussed below.
About 1 to 100 mg. of compound or mixture of compounds of Formula I or a
physiologically acceptable salt is compounded with a physiologically
acceptable vehicle, carrier, excipient, binder, preservative, stabilizer,
flavor, etc., in a unit dosage form as called for by accepted
pharmaceutical practice. The amount of active substance in these
compositions or preparations is such that a suitable dosage in the range
indicated is obtained.
Illustrative of the adjuvants which can be incorporated in tablets,
capsules and the like are the following: a binder such as gum tragacanth,
acacia, corn starch or gelatin; an excipient such as microcrystalline
cellulose; a disintegrating agent such as corn starch, pregelatinized
starch, alginic acid and the like; a lubricant such as magnesium stearate;
a sweetening agent such as sucrose, lactose or saccharin; a flavoring
agent such as peppermint, oil of wintergreen or cherry. When the dosage
unitform is a capsule, it may contain, in addition to materials of the
above type, a liquid carrier such as fatty oil. Various other materials
may be present as coatings or to otherwise modify the physical form of the
dosage unit. For instance, tablets may be coated with shellac, sugar or
both. A syrup or elixir may contain the active compound, sucrose as a
sweetening agent, methyl and propyl parabens as preservatives, a dye and a
flavoring such as cherry or orange flavor.
Sterile compositions for injection can be formulated according to
conventional pharmaceutical practice by dissolving or suspending the
active substance in a vehicle such as water for injection, a naturally
occuring vegetable oil like sesame oil, coconut oil, peanut oil,
cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or
the like. Buffers, preservatives, antioxidants and the like can be
incorporated as required.
FORMULATION EXAMPLES
Typical Pharmaceutical Compositions Containing the Compound of the
Invention
A: Dry Filled Capsules Containing 50 mg of Active Ingredient Per Capsule
______________________________________
Ingredient Amount per Capsule (mg)
______________________________________
Compound I 50
Lactose 149
Magnesium stearate
1
Capsule (size No. 1)
200
______________________________________
Compound I can be reduces to a No. 60 powder and the lactose and magnesium
stearate can then be passed through a No. 60 blotting cloth onto the
powder. The combined ingredients can then be mixed for about 10 minutes
and fikkes into a No. 1 dry gelatin capsule.
B: Tablet
A typical tablet would contain Compound I (25 mg), pregelatinized starch
USP (82 mg), microcrystaline cellulose (82 mg) and magnesium stearate (1
mg).
C: Suppository Formulation
A typical suppository formulations for rectal administration can contain
Compound I (1-25 mg), butylated hydroxyanisole (0.08-1.0 mg), disodium
calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg).
Other suppository formulations can be made by substituting, for example,
butylated hydroxytoluene (0.04-0.08 mg) for the disodium clacium edetate
and a hydrogenated vegetable oil (675-1400 mg) such as Suppocire L,
Wecobee FS, Wecobee M, Witepsols, and the like, for the polyethylene
glucol. Further, these suppository formulations can also include another
active ingredient such as another antihypertensive and/or a diuretic
and/or an angiotensin converting enzyme and/or a calcium channel blocker
in pharmaceutically effective amounts.
D: Injection
A typical injectable formulation would contain Compound I (5.42 mg), sodium
phosphate dibasic anhydrous (11.4 mg) benzyl alcohol (0.01 ml) and water
for injection (1.0 ml). Such an injectable formulation can also include a
pharmaceutically effective amount of another active ingredient such as
another antihypertansive and/or a diuretic and/or an angiotensin
converting enzyme inhibitor and/or a calcium channel blocker.
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